Project Summary/Abstract A large number of studies over the last 14 years show that orexin neurons play an important role in reward processing and drug abuse. Although these studies show that orexin-1 receptor (OxR1) signaling is particularly involved in the motivation for many drugs of abuse, none have linked this system to the persistent, chronically relapsing nature of addiction. Here, we extend studies from the previous terms of this project to tackle this important issue. We recently found that the intermittent access (IntA) cocaine self-administration paradigm produces a strong, multiphenotype addiction-like state as well as increased numbers of orexin-expressing neurons. Importantly we find that the IntA-induced increase in addiction behaviors and orexin expression are persistent (>30d of abstinence). We also find that chronic administration of an OxR1 antagonist during IntA blocks the increased demand that this paradigm normally produces. Here, we propose to more fully characterize the IntA-linked addiction profile and induced-orexin neurons following 30d abstinence. We also will examine the contribution of OxR1 and OxR2 signaling in ventral tegmental area (VTA) and paraventricular thalamus (PVT), two reward-related areas previously linked to orexin function, in persistent addiction behaviors after IntA. Finally, we will test whether the FDA-approved dual orexin receptor antagonist, Belsomra? (suvorexant), is effective in acutely decreasing addiction behaviors, and in preventing the transition from a moderate to a severe addiction profile. Together, the proposed experiments are a natural and important extension of the prior studies in this project and will represent an important step forward in the development of an orexin-based treatment for cocaine addiction.